(1; R1 = Me, R2 = Me)

[7417-67-6]  · C3H6N2O2  · N-Methyl-N-nitrosoacetamide  · (MW 102.11) (2; R1 = Me, R2 = Pr)

[16395-81-6]  · C5H10N2O2  · N-Methyl-N-nitrosobutyramide  · (MW 130.17) (3; R1 = Bu, R2 = Me)

[14300-06-2]  · C6H12N2O2  · N-Butyl-N-nitrosoacetamide  · (MW 144.20) (4; R1 = Bu, R2 = Et)

[99389-05-6]  · C7H14N2O2  · N-Butyl-N-nitrosopropionamide  · (MW 158.23)

(alkylating agent;2 source of diazomethane;3 useful as activated acylating agent;4 precursor to esters and alkenes1a,5,6)

Physical Data: (1) bp 115-116 °C/760 mmHg. (2) bp 59-60 °C/14 mmHg. (3) bp 35-37 °C/0.1 mmHg. (4) bp 63-65 °C/6 mmHg.

Solubility: sol benzene, Et2O, CHCl3, acetone.

Preparative Methods: nitrosation of N-alkyl amides with Sodium Nitrite/acid mixtures, Nitrosyl Chloride, or Nitrogen Dioxide.10 N-Deprotonation of the amide with n-Butyllithium or Sodium Hydride, followed by treatment with nitrosonium salts11 or Nitrogen Dioxide,12 is a second approach that is particularly useful in the preparation of thermally labile nitrosoamides.

Handling, Storage, and Precautions: the stability of N-nitrosoamides is dependent largely on steric factors.1a,7 For N-nitrosoacetamides, RN(NO)COMe, compounds with a primary N-alkyl group are stable for weeks at 25 °C if kept dry; decomposition occurs at approx 75 °C. Compounds with secondary N-alkyl groups decompose at 25 °C (t1/2 about 0.5 h). Compounds with tertiary alkyl groups must be synthesized and utilized at low temperatures. Alkyl substitution on the acyl group leads to increases in decomposition rates similar to those for the alkyl group. N-Nitrosoamides are decomposed by acids and bases. Nitrosoamides bearing small alkyl groups possess potent mutagenic8 and carcinogenic9 (local and systemic) activity. Use in a fume hood and take reasonable precautions.

Alkylation Reactions.

N-Alkyl-N-nitrosoamides (1) are thermolabile compounds which undergo first-order decay7 to yield, via diazotate esters (5), diazonium carboxylate ion pairs (6) as reaction intermediates (eq 1).13 If the alkyl group is allylic, secondary, or tertiary, highly active nitrogen-separated ion pairs (7) are formed;13a the carbocations can subsequently undergo the usual types of reactions: nucleophilic capture by solvent or counterion, proton elimination, and skeletal rearrangement (eq 2).

Analogs of the nitrosoamides are known, and the counterions can be derived from a range of acids (carboxylic, carbonic, carbamic, sulfonic, etc.). In nonreactive solvents, ion pair combination to give the corresponding ester can be the major reaction (eq 2); the esters are usually formed with retention of configuration. Further, a nitrosoamide labeled in the carbonyl group with 18O decomposes to yield ester with a preponderance of 18O in the carbonyl group.13a If the solvent (and the carbocation) are sufficiently reactive, solvent capture becomes the major reaction.2b,13a For example, the decomposition of N-benzyl-N-nitrosotrifluoromethanesulfonamide (8) in benzene (t1/2 &AApprox; 10-20 min) at 30 °C yields ~60% diphenylmethane,2b and decomposition in acetonitrile yields the nitrilium salt.2b The nitrosoamide decomposition, thus, can produce a series of alkylating agents of differing activity: carbocations, nitrilium salts (and related products from relatively unreactive solvents), and alkyl sulfonate esters. The nitrosoamide decomposition is a method for the production of highly reactive alkylating agents under mild conditions in nonpolar solvents and in the absence of electrophilic agents;2b it lends itself especially to transformations of isotopically labeled amines and chiral amines.

Acylation Reactions.

N-Nitrosation of amides markedly activates the amide group to cleavage by nucleophiles. For example, thiolate ions react at rt with nitrosoamides to afford S-alkyl and S-aryl thioesters in good yields (eq 3);3a byproducts arising from N- to S-trans-nitrosations are rarely formed.3a

Amides of general formula R1CONHR1 can be nitrosated and the resulting nitrosoamides converted into R1CONH2, R1CONHR2, or R1CONR2R3 by reaction with ammonia or an amine.14 The overall two-step reaction is almost quantitative.14 By this approach, N-alkyl amides are formed without the competitive O- and C-alkylations that may occur in the direct alkylation of amides. Analogous reactions with aromatic amines are less successful.14 In another application, racemic carboxylic acids have been converted into diastereomeric amides; separation of the diastereomers by chromatography and subsequent deamination via the nitrosoamide route, followed by ester hydrolysis, affords essentially the pure chiral carboxylic acids.15

N-Nitrosoamides react with alkoxide-alcohol mixtures to yield diazoalkanes corresponding to the amine moiety of the amide (eq 4).24 This approach is widely used to synthesize this very useful class of alkylating agents (see Diazomethane).

Acylation and Alkylation Reactions.

The generation of highly reactive carbocations from N-nitrosoamides lends itself to the active-site mapping and inhibition of enzymes.4b,c In these studies, R1 and R2 are recognized by the binding site of the enzyme, and the carbocation formed alkylates nucleophilic centers in the active site such as amide linkages and amino acid side chains.4b

Miscellaneous Reactions.

The acyl groups of nitrosoamides are readily reduced to primary alcohols (50-82% yields) by Sodium Borohydride at 25 °C.16 Reduction to the corresponding hydrazide is achieved with Zinc-Acetic Acid (~80%)17 and Titanium(IV) Chloride/Magnesium (~60%).16 In nonpolar solvents at 80-100 °C, nitrosoamides decompose in the presence of rhodium(II) carboxylates (see Dirhodium(II) Tetraacetate) to yield, ultimately, the corresponding alkene (eq 5).6

Photolysis of nitrosoamides results in initial scission of the N-N bond followed by hydrogen abstraction from the solvent by the amido radical. In the final step the nitric oxide generated in the first step reacts with the new carbon radical to yield ketones from alcohols,18 and oximes, nitrosoalkane dimers, and nitrite esters from hydrocarbons.19

Related Alkylating Agents.

A number of alkylating agents utilizing deaminatively formed carbocations are available. Compounds with replaceable protons are alkylated by syn- and anti-alkanediazotate salts,20 and by N-alkyl-N-nitrososulfamates.21 Conditions can be found for alkylation by N-alkyl-N-nitro-O-acylhydroxylamines22 and the corresponding N-nitroso analogs.13a,23 These methods are mechanistically related to alkylations with diazoalkanes (see Diazomethane) or with 3-alkyl-1-p-tolyltriazenes (see 3-Methyl-1-p-tolyltriazene).

The thermal decomposition of N-nitroamides in nonreactive solvents yields the same ester/alkene products as are formed from the corresponding N-nitrosoamides via analogous intermediates. The nitroamides are, like their nitroso analogs, good acylating agents of nucleophiles.14

Related Reagents.

Diazomethane; 1-Methyl-3-nitro-1-nitrosoguanidine; N-[N-Methyl-N-nitroso(aminomethyl)]benzamide; N-Methyl-N-nitroso-p-toluenesulfonamide; 3-Methyl-1-p-tolyltriazene; N-Nitrosodimethylamine; Nitrosonium Tetrafluoroborate; Nitrosyl Chloride; Sodium Nitrite; Trimethylsilyldiazomethane.

1. (a) White, E. H.; Woodcock, D. J. In The Chemistry of the Amino Group; Patai, S., Ed.; Wiley: New York, 1968; pp 440-483. (b) Keating, J. T.; Skell, P. S. In Carbonium Ions, Olah, G. A.; Schleyer, P. v. R., Eds.; Wiley: New York, 1970; Vol. 2, pp 573-653. (c) Friedman, L. In Carbonium Ions; Olah, G. A.; Schleyer, P. v. R., Eds.; Wiley: New York, 1970; Vol. 2, pp 655-713. (d) Moss, R. A. ACR 1974, 7, 421.
2. (a) Cohen, T.; Daniewski, A. R.; Solash, J. JOC 1980, 45, 2847. (b) White, E. H.; DePinto, J. T.; Polito, A. J.; Bauer, I.; Roswell, D. F. JACS 1988, 110, 3708. (c) Paal, C.; Lowitsh, L. CB 1897, 30, 869.
3. (a) McPhee, W. D.; Klingsberg, E. OSC 1955, 3, 119. (b) Huisgen, R.; Reinertshofer J. LA 1952, 575, 174.
4. (a) Berenguer, R.; Garcia, J.; Vilarrasa, J. S 1989, 305. (b) White, E. H.; Jelinski, L. W.; Politzer, I. R.; Branchini, B. R.; Roswell, D. F. JACS 1981, 103, 4231. (c) Donadio, S.; Perks, H. M.; Tsuchiya, K.; White, E. H. B 1985, 24, 2447.
5. White, E. H. JACS 1955, 77, 6011.
6. Godfrey, A. G.; Ganem, B. JACS 1990, 112, 3717.
7. Huisgen, R.; Reimlinger, H. LA 1956, 599, 161.
8. Lee, K.; Gold B.; Mirvish, S. S. Mutat. Res. 1977, 48, 131.
9. Preussman, R.; Stewart, B. W. in Chemical Carcinogenesis; Searle, C. Ed.; American Chemical Society: Washington, 1984; pp 643-828.
10. White, E. H. JACS 1955, 77, 6008.
11. Simpson, J. M.; Kopp, D. C.; Chapman, T. M. S 1979, 100.
12. White, E. H.; Stuber, J. E. JACS 1963, 85, 2168.
13. (a) White, E. H.; Field, K. W.; Hendrickson, W. H.; Dzadzic, P.; Roswell, D. F.; Paik, S.; Mullen, P. W. JACS 1992, 114, 8023. (b) Kirmse, W.; Moench, D. CB 1991, 124, 237. (c) Brosch, D.; Kirmse, W. JOC 1991, 56, 907.
14. Garcia, J.; González, J.; Segura, R.; Urpí, F.; Vilarrasa, J. JOC 1984, 49, 3322.
15. Schmidtchen, F. P.; Rauschenbach, P.; Simon, H. ZN(B) 1977, 32B, 98.
16. Saavedra, J. E. JOC 1979, 44, 860.
17. Garcia, J.; Vilarrasa, J. TL 1987, 28, 341.
18. Kuhn, L. P.; Kleinspehn, G. G.; Duckworth, A. C. JACS 1967, 89, 3858.
19. Chow, Y. L.; Tam, N. S.; Lee, A. C. H. CJC 1969, 47, 2441.
20. (a) White, E. H.; Ryan, T. J.; Field, K. W.; JACS 1972, 94, 1360. (b) Suhr, H. CB 1963, 96, 1720. (c) Moss, R. A. Chem. Eng. News 1971, 49(48), 28.
21. White, E. H.; Li, M.; Lu, S. JOC 1992, 57, 1252.
22. White, E. H.; Reefer, J.; Erickson, R. H.; Dzadzic, P. M. JOC 1984, 49, 4872.
23. White, E. H.; Ribi, M.; Cho, L. K.; Egger, N.; Dzadzic, P. M.; Todd, M. D. JOC 1984, 49, 4866.
24. Eistert, B.; Regitz, M.; Heck, G.; Schwall, H. MOC 1968, 10/4, 473.

Emil H. White & Ron W. Darbeau

The Johns Hopkins University, Baltimore, MD, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.